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Tissue repair (1)

Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s P rogrammes at the University of Pécs and at the University of Debrecen Identification number : TÁMOP-4.1.2-08/1/A-2009-0011.

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Tissue repair (1)

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  1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

  2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Dr. Judit Pongrácz Threedimensionaltissuecultures and tissueengineering – Lecture 17 Tissuerepair(1)

  3. Stem cells in the bone marrow • Hematopoetic stem cells (HSC) • Mesenchymal stem cells (MSC) • „Side population” • Multipotent adult progenitor cells (MAPC)

  4. Therapeuticindicationsforstemcelltherapy • Cardiovascular and ischemic diseases • Diabetes • Hematopoietic diseases • Liver diseases • Orthopedics • More than 25 000 hematopoietic SC transplantations are performed yearly

  5. Embryonic stemcell • Advantages of Embryonic SC: • Pluripotent • easy to isolate • highly productive in culture • high capacity to integrate into fetal tissue • Disadvantages: • immune rejection • Differentiation into inadequate cell types • tumors induction • Risk of contamination

  6. Germ stem cells • Germ stem cells • Pluripotent • Scarce harvesting source • May develop embryonic teratoma cells • Adult stem cells • Advantages: • Multipotent • Greater differentiation potential • Less likely induce immune rejection reactions • May be stimulated by drugs • Disadvantages: • Scarce and difficult to isolate • Grow slowly, differentiate poorly in culture • Difficult to handle and produce in adequate amounts for transplantation

  7. Hemopoetic Cell Transplantation(HCT) • Diseases treatable with HCT: • Hemopoetic malignancies • Autotransplantation • Allogenic transplantation • Herediteryimmunodeficiencies • Aplastic hematologic diseases • BM-derived stem cells were detected in numerous organs after transplantation or injury (sex-mismatched transplantation)

  8. Hematopoetic stem cells • Stem cell theory emerged in the 50’s • Located in the BM • CD34+, CD133+, c-kit+, CD38-, CD45- • Worldwide databases available of BM donors

  9. General principles of stem cell therapy 5. Reinfusion Thawed stem cells are reinfused into the patient 1. Collection Stem cells are collected from the patient’s bone marrow or blood 4. Chemotherapy High dose chemotherapy and/or radiation is given to the patient 2. Processing Blood or bone marrow is processed in the laboratory to purify and concentrate the stem cells 3. Cryopreservation Blood or bone marrow is frozen to preserve it

  10. Bonerepairwithstemcells Baseline G-CSF mobilization G-CSF Blood Blood CXCL12 G-CSFR CXCR4 Perivascular cells VCAM-1 Monocyte Monocyte VLA-4 HSPC HSPC c-kit kitL C3a uPAR Osteolineagecells Bone Bone

  11. Cartilageregeneration TGF-b Cultured chondrocytes injected under patch Tissue culture ofisolated stemcellsinbioreactors Periosteal patch harvested from tibia

  12. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Dr. Judit Pongrácz Threedimensionaltissuecultures and tissueengineering – Lecture 18 Tissuerepair(2)

  13. Liver repair Functions of theliver: Metabolism Energy homeostasis, glycogen production and storage Detoxification Bile production Plasma protein synthesis In case of injury the intrinsic repair capacity may be insufficient. Today thelong-term therapeutic option for liver failure istransplantation.

  14. Causes of liver failure Toxic compounds Drugs Alcohol Chemicals Infectious diseases Hepatitis viruses Bacteria Parasites (malaria) Intrinsic causes Genetic Autoimmune (primary biliarycirrhosis)

  15. Liver transplantation Today theonly long term therapy for liver failure Immuno-suppression needed Patient is prone to infections Serious side-effects of immunosuppressant drugs Worldwide shortage of donors

  16. Potentialincellulartherapy of liverfailure • Less invasivethanorgantransplantation • Can be repeatedmultipletimes • Limiting factor is theinability of • Producing a sufficientlylargenumber of hepatocytes • Keephepatocytesreadyforuseon-demand • Expansion of existinghepatocytes • Usingstemcellstodifferentiatehepatocytes

  17. Using stem cells for liver regeneration • BM stem cells • Hematopoetic SC • Mesenchymal SC • Stem/progenitor cells in the liver • Embryonic stem cells

  18. HSC and liver regeneration • BM resident HSC contains a population expressing SC markers (CD34, c-kit) and a-fetoprotein (aFP, liver progenitor cell marker) • When BMSC were cultured in the presence of hepatocyte growth factor (HGF) showed hepatocyte-like characteristics • These experiments were done in rodents and humans

  19. MSC and liver regeneration • MSC subpopulation multipotent adult progenitor cells (MAPC) • Human MAPC differentiated into hepatocyte-like cells in the presence of HGF • Substantial delay of the differentiation • Therefore the potential of clinical usage is questionable

  20. Cultured HSC differentiateintohepatocytes Autologousculturedhepatocytes Patient Hepatocytes Liverdamage Bloodor BM Cellulardifferentiation Cellseeding/Inoculation Isolation of StemCells Culture + HGF

  21. Human trials • Cases: • Livercancer • Hepatitis B or C • Cirrhosis (alcoholic, drugor primer) • BMSC: • Unsortedmononuclearcells • Sorted CD34+ or CD133+ cells • Route of administration: • Peripheralvein • Portalvein • Hepaticartery • Results: • Mostlywelltolerated • ImprovementsinChild-Pughscore, albumin, AST, ALP, bilirubin, clotting

  22. Injury-induced differentiation of BMSC (animal models) • Murine model: sex-mismatched donor BMSC transplantation in a hereditarylethal liver disease model (tyrosinemia, FAH-/-) • 1/3 of the hepatocytes were of donor origin after 22weeks • In an induced liver cirrhosis model, 25% of hepatocytes were of donor origin after just 4weeks

  23. Conclusions • Clinical application is not well established and not ready for routine therapy • Which cases? • Which cells? • Which administration route? • Risks and benefits of autologous cellular therapy in liver failure?

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